The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital is a Comprehensive Cancer Center, combining hospital and research laboratories under one roof in a single independent organization. The hospital comprises 180 beds, an outpatient clinic and a large radiotherapy department. Facilities for clinical research include a large patient database, clinical data management, extensive diagnostic facilities, a pharmacy with a production unit for experimental drugs, and active research groups in pharmacy, epidemiology and psychosocial oncology. The laboratory covers all major areas of cancer research, with special emphasis on cell-based screens, mouse tumour models, cell biology, structural biology, and immunology. Translational research is an integral activity of many research groups and is fostered by collaborations between clinical and basic scientists. Teaching at many levels is part our daily business.
Understanding cancer: basic research at the NKI
The basic research at the NKI aims for a more profound understanding of how cancer arises, and strives to translate this knowledge into new approaches to diagnosing and treating cancer. This encompasses many scientific themes in tumor-cell biology, notably how genetic mutations arise, in which genes, and with what consequences; how genes are organized in the nucleus and regulated, and how this regulation may go wrong in cancer; signaling in normal and cancer cells – at the cell surface and the transmission of signals to the cell interior; cell fate; cell division; programmed cell death (apoptosis); tumor growth and metastasis; and resistance to cancer treatment.
Cutting-edge technologies
Scientists at the NKI are among the world’s most talented inventors and users of new technologies. This can involve gadgets and reagents for use at the laboratory bench, the creation of new animal models, or new high-throughput devices in centralized facilities. The NKI has particular expertise in using and generating new animal models for cancer. These are helping to provide insights into many aspects of cancer biology, especially in understanding how the effects of different genetic mutations can combine to promote tumor development. They also serve as tools for the pre-clinical testing of new therapies and drugs. The NKI’s animal models are valuable not only to NKI researchers but also to other research institutes and pharmaceutical companies for the testing of new anticancer drugs.
Functional screens
NKI scientists use various techniques for altering the action of individual genes in both laboratory cell cultures and in animal models. This enables them to identify a gene’s normal function and to mimic the effects of mutation, which could either enhance or reduce a gene’s activity.
To enhance the activity of a particular gene, for example, NKI scientists can use transgenic mouse technology to introduce molecular machinery to switch a gene on and maintain its activity at high levels, even at stages in development when it is normally switched off. Conversely, NKI scientists use a technique known as RNA interference (RNAi) to selectively switch off the activity of a particular gene, or genes, and examine the consequences for various cell processes. This involves introducing small pieces of RNA to effectively silence individual genes.
The NKI has a collection of over 30,000 small RNA pieces, which in total correspond to all human genes. Besides contributing to understanding gene function, this technique also helps to identify new targets for drug development.
Understanding mutations – the trigger for cancer
Genetic mutations lie at the heart of tumor formation. As mutations accumulate in genes that are critical to cell growth and signaling, cells stop producing key proteins, or produce abnormal versions, and begin to behave incorrectly. They break free of normal constraints on cell growth and division and spread to other parts of the body. Mutations that result in cancer can either be spontaneous, appearing in a cell for the first time, or can be inherited by children from their parents, which increases the risk of developing a particular form of cancer, such as in the breast or colon.
On a basic level, NKI scientists are investigating the effects of genetic mutations on processes that normally maintain cells in good health, for example, the repair of damage or other alterations to DNA. When chemicals or radiation damage the nucleotide building blocks of DNA, a complex of proteins normally repairs the damage by replacing altered nucleotides with new ones. A similar repair process occurs when enzymes responsible for replicating DNA make an error and insert the wrong nucleotide into the DNA sequence, which can occur if mutations arise in one or more of the enzymes. Using in vitro cell culture, functional screens, biochemistry and protein crystallography, NKI scientists are investigating the processes leading to DNA damage or replication errors, and the effects of mutations on DNA repair proteins.
Cell signaling
Cells do not exist in isolation. Rather, they are in continuous communication with their surroundings, receiving and responding to signals from hormones, cytokines, and other cells. NKI scientists are investigating the mechanisms by which signals are relayed to the cell interior, and how these can go wrong in cancer cells. Research into abnormalities in the receptors on the surface of breast cancer cells has led to the creation of a new screening tool for patients which can determine how well they may respond to hormone treatment.
The body’s immune defenses, best known for their role in fighting infections, are also important in protecting against cancer. This too depends upon signaling at the surface of the immune system’s ‘soldiers’, the lymphocytes. These can ‘recognize’ tumor cells as abnormal and alert and attract other cells to kill the cancer cells. None of this would occur without extensive signals being exchanged between different cells, through receptors on their surfaces and the release of molecules called cytokines. NKI scientists are searching for ways to enhance these processes, including the design of novel cancer vaccines, which are currently being tested in animals before moving to clinical trials.
Tumor growth and metastasis
The ability of tumors to grow and ruthlessly destroy the body’s vital organs is the key feature that distinguishes them from normal tissues. NKI researchers are investigating how normal cells start to ignore the signals that would normally prevent a cell dividing too often. Alongside this, they are studying how cells start to move around the body and grow in new tissues, a process known as metastasis. Advances in understanding these processes may one day lead to new approaches to cancer treatment.
Improving cancer treatment: clinical research at the NKI
Clinical research aims to introduce new forms of treatment into the clinic and to improve existing ones. Highly trained clinical and auxiliary professionals, multidisciplinary patient reviews, specially trained oncology nurses, and excellent support facilities for clinical trials allow many clinical trials to be performed at the hospital.
Improving diagnosis and prognosis
Through collaboration with surgeons, the NKI-AVL’s pathology department has amassed an impressive bank of tumor tissue from breast cancer patients. This has allowed researchers to develop new tests for predicting metastasis using DNA microarray analysis, a method that is now widely used in the laboratory, but is only just beginning to have an impact in the clinic. This works by detecting patterns in gene activity that differ between tumor cells and normal tissues.
NKI researchers are now also applying microarray technology to predict the effects of different drugs on a tumor. These studies would not be possible without the institute’s bioinformaticians, who analyze the data and develop the computer algorithms needed for making confident predictions.
Meanwhile, NKI researchers are also searching for new diagnostic markers in biological fluids – mainly blood, urine and cerebrospinal fluid. The aim is to develop non-invasive ways of identifying the type of tumor a patient has, and the extent to which it has spread beyond its original site.
Therapies of the future
Cancer treatments of the future are likely to be more finely tuned to the needs of the individual patient than at present. Most existing anticancer drugs target rapidly dividing cells indiscriminately, which is why they can have severe side effects such as nausea, dizziness, loss of taste sensation, fatigue, and hair loss. Radiotherapy too can have long-term side effects on the tissues surrounding tumors, including causing secondary cancers and heart disease.
The NKI therefore places great emphasis on the goal of creating new approaches to cancer therapy that reduce side effects and enhance patient survival. One approach is to make existing treatments more effective by combining two or more different modalities, such as chemotherapy and radiotherapy. This allows smaller doses of either to be given to the patient, and may help to avoid long-term sideeffects.
Similarly, the use of photodynamic therapy, isolated limb perfusion, and hyperthermic intra peritoneal chemotherapy (HIPEC) enable chemotherapy to be given at high dose in more localized parts of the body, thus sparing other organs from exposure.
These treatments still fail, however, to distinguish between most normal tissues and tumors. NKI scientists are therefore exploring new ideas for targeting therapy specifically at cancer cells. These are tested in animal models first, to gauge safety and effectiveness, before entering clinical trials. One example is the use of DNA-based vaccines against cervical cancer and melanoma, to trigger the immune system to target tumors, combined with low doses of radiation to boost the influx of immune cells to a tumor site.
Overcoming resistance
Scientists at the NKI are working to enhance drug uptake into the body so as to enable patients to take drugs orally rather than by injection, and to raise the dose and extend the time that drugs are active in the body. They are also attempting to overcome the problem of drug resistance, which often arises through mutation in a patient’s tumor. One strategy is to find and design drugs that attack alternative weak spots in a cancer cell and render the tumor more sensitive to treatment.
Through imaging technology such as MRI and PET, patients can be monitored to see whether or not the drug is killing and shrinking a tumor, enabling clinicians to monitor the success of a particular treatment.
Protecting against cancer
The devastating effect of cancer sometimes leads patients or their relatives to volunteer as subjects for cancer research. Following the availability of new genetics tools during the late 1980s and 1990s, the NKI-AVL set up a Family Cancer Clinic where family members receive genetic counseling on their own risk of developing cancer. Molecular biologists and epidemiologists at the NKI are following families affected by cancer in order to identify new mutations associated with the disease, and to pinpoint how environmental factors such as diet, exercise and hormones may raise the risk of developing cancer, or serve as protection.
Coping with cancer
Being diagnosed for cancer changes one’s whole perspective on life. Not only the patient, but also their friends and family, have to cope with the diagnosis and treatment. Research into coping mechanisms has led to changes in treatment and care that help patients and their close relatives.
Forging ahead
The NKI-AVL is proud of its position as one of The Netherlands’ foremost biomedical research institutions, dedicated to improving the treatment and care of patients with cancer, and helping healthy individuals to avoid cancer in future. Its clinical services operate to the highest international standards, and continue to extend the boundaries of what can be done for cancer patients. Its scientific achievements are celebrated internationally through awards and highly cited publications in peer-reviewed journals. With well-integrated clinical and basic research operations, the NKI-AVL aims to have a critical impact on cancer in the future.